Aliskiren (I) is a second generation renin inhibitor with renin-angiotensin system (RAS) as its target. It's used clinically in the form of Aliskiren hemifumarate (Rasilez®) and was approved by FDA in May, 2007.
Aliskiren has the chemical name: (2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methyloctanamide (CAS No.: 173334-57-1). Its chemical structure is illustrated with Formula I given below:

The method of preparation for Aliskiren and its intermediates has been reported in U.S. Pat. No. 7,132,569, WO0208172, U.S. Pat. No. 5,559,111, (equivalent patent to CN1266118), U.S. Pat. No. 5,606,078, CN01016253, WO2007/045421, EP2002874, Helvetica ChimicaActa (2005, 3263-13273).
In U.S. Pat. No. 7,132,569, WO0208172 et al., the preparation of Aliskiren (I) comprises the following steps as described in reaction scheme 1: coupling 2-(3-methoxypropoxy)-4-((R)-2-(bromomethyl)-3-methylbutyl)-1-methoxybenzene (II) with (2S,4E)-5-chloro-2-isopropyl-4-pentenoic acid derivative (III) to obtain the compound of formula IV; halolactonization of the compound of formula IV to obtain the compound of formula V; then substituting the compound of formula V with azide to obtain the compound of formula VI; ring-opening the compound of formula VI with 3-amino-2,2-dimethylpropionamide (VII) in the presence of 2-hydroxypyridine and triethylamine to obtain the compound of formula VIII and a final catalytic hydrogenation of the compound of formula VIII to obtain Aliskiren (I). This preparation process is illustrated in Reaction Scheme 1.

In the patented preparation described above, chiral starting materials with the compounds of formula II and III are utilized to obtain the compound of formula IV. However, the reactions followed after the preparation of the compound of formula IV, such as the halolactonization and especially the substitutive reaction between the compound of formula V and azide, have problems of low yields and numerous by-products, which is not conducive to industrial scale production.
U.S. Pat. No. 5,559,111 (equivalent patent CN1266118) and U.S. Pat. No. 5,606,078 et al. report the preparation of the compound of formula XI via Grignard reaction with 4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene (IX) and the compound of formula X as starting materials as illustrated in Reaction Scheme 2:

In the patented preparation described above, there are multiple reaction steps in the preparation of the compound of formula X from the compound of formula XII. The key steps, as described in Reaction Scheme 3, involve selective reduction agents such as sodium tri-tert-butoxyaluminum hydride and diisobutylaluminium hydride to prepare aldehyde and the reaction conditions need to be very well-controlled.

The compound of formula XI prepared by reaction scheme 2 could then be convened into Aliskiren (I) after multiple catalytic hydrogenation, protection and de-protection. In this method of preparation, a stepwise catalytic hydrogenation, azido reduction and dehydroxylation were implemented to reduce by-products during the catalytic hydrogenation. In addition, it is necessary to protect and de-protect the free hydroxyl group during the preparation. This synthetic scheme has disadvantage of multiple synthetic steps, tedious operation, lengthy overall reaction duration, low yield and particularly high production cost for the starting compound of formula X.
WO2007/045421 has reported an improved preparation method in which the starting material 4-bromo-1-methoxy-2-(3-methoxypropoxy)benzene (IX) firstly reacts with the compound of formula XIII via Grignard reaction to obtain the compound of formula XIV, and then followed by catalytic hydrogenation and ketone reduction to yield the compound of formula XV-A, as illustrated in Reaction Scheme 4:

In the above preparation, expensive reagents, such as sodium tri-tert-butoxyaluminum hydride and diisobutylaluminium hydride were eliminated, but additional synthetic steps were introduced. In addition, the preparation of the compound of formula XV-A prepared from the compound of formula XIV via ketone reduction required extended reaction time, great amount of catalyst with multiple small addition and good operation skills.
EP2062874A1 provides a method in preparing the compound of formula XVI. In this method, the compound of formula XVII is obtained from the compound of formula XVI via halogenation. A corresponding Grignard reagent is firstly prepared from the compound of formula IX or XVII reacting with magnesium, which is then couples with another chemical in the presence of the metal catalyst iron(III) acetylacetonate (Fe(acac)3) to obtain the compound of formula XVIII as described in Reaction Scheme 5:

In EP2062874A1, the compound of formula XVIII reacts with 3-amino-2,2-dimethylpropionamide (VII). The resulted product is then through reduction of the azio group to obtain Aliskiren (I). In this patent, detailed experimental protocol was not provided although N-methylpyrrolidone was mentioned as solvent. We found: 1) it is difficult to prepare the Grgnard reagent from the compound of formula IX; 2) the compounds of formula XVII and XVIII are not quite stable in the presence of iron(III) acetylacetonate. In addition, the yield in preparing the compound of formula XVIII was extremely low.
In summary, there are disadvantage among the current available methods in preparing Aliskiren, such as expensive starting materials, complicated reaction operations, difficulties in controlling by-products and lengthy reaction time. Therefore, its necessary and technically meaningful to develop a novel method for Aliskiren and its intermediates preparation to avoid current disadvantage.